Erythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasm
Johanne Poisson, … , Chantal M. Boulanger, Pierre-Emmanuel Rautou
Johanne Poisson, … , Chantal M. Boulanger, Pierre-Emmanuel Rautou
Published February 11, 2020
Citation Information: J Clin Invest. 2020;130(5):2630-2643. https://doi.org/10.1172/JCI124566.
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Research Article Cardiology Hematology

Erythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasm

Abstract

Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPNs). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPNs suggests that vascular function is altered. The consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice resulting from a disturbed endothelial NO pathway and increased endothelial oxidative stress. This response was reproduced in WT mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for their effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes suppressed their effect on oxidative stress. Antioxidants such as simvastatin and N-acetyl cysteine improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPNs are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears to be a promising therapeutic strategy in this setting.

Authors

Johanne Poisson, Marion Tanguy, Hortense Davy, Fatoumata Camara, Marie-Belle El Mdawar, Marouane Kheloufi, Tracy Dagher, Cécile Devue, Juliette Lasselin, Aurélie Plessier, Salma Merchant, Olivier Blanc-Brude, Michèle Souyri, Nathalie Mougenot, Florent Dingli, Damarys Loew, Stephane N. Hatem, Chloé James, Jean-Luc Villeval, Chantal M. Boulanger, Pierre-Emmanuel Rautou

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Figure 2

JAK2V617F specifically expressed in hematopoietic, but not endothelial, cells increases arterial contraction.

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JAK2V617F specifically expressed in hematopoietic, but not endothelial, ...
(A and F) Representative images of the spleen. Blood cell count of 10- to 13-week-old control mice (Jak2WT, n = 7) and Jak2V617F Flex/WT VE-cadherin-Cre-ERT2 mice (Jak2V617F EC, n = 7) (B–D) and of 13- to 15-week-old chimeric C57BL/6 mice transplanted with bone marrow of WT mice (Jak2WT, n = 5) or of Jak2V617F HC-EC mice (Jak2V617F HC, n = 5) (G–I). Data are expressed as median with IQR. Cumulative dose-response curve to phenylephrine of aortas from Jak2WT (n = 7) and Jak2V617F EC mice (n = 7) (E) and from Jak2WT (n = 5) and Jak2V617F HC mice (n = 5) (J). Quantitative data are expressed as median with IQR, and cumulative dose-response curves are expressed as mean with SEM. *P < 0.05, **P < 0.01. Cumulative dose-response curves were compared using ANOVA for repeated measures, and other data were compared using the Mann-Whitney U test. All tests were 2 sided.